A variety of methods and sensors have been developed for chemical, biochemical, biological or biochemical analysis, control and detection. Biological species of interest include molecules, for example: sugars, nucleic acids, proteins, DNA, RNA, various toxins, bacteria, parasites, fungi, viruses, etc. The development of the claimed detection methods will have significant impact on broad range of applications related to medical diagnostic, drug development, food control and safety, the environment, energy production, and security. However, the invention has even broader range of applicability. Development of new nanostructured materials together with the emerging advances in micro, nano and superlattice structures and electronics create a new avenue for construction of more advanced methods and sensors.
There exist a number of known methods for detecting biochemical materials. The most common are: optical absorption and reflection, Raman spectroscopy, photoluminescence, fluorescence, electrophoresis, mass spectroscopy, ion mobility etc. The current generation of sensors is mostly constructed of a transducer in combination with a biological active surface. Many of these rely on specific ligand antiligand reactions as the detection mechanism. Others rely on electronic signals for detection, using DC or AC potentials, and detecting change in impedance, with or without using mediators for charge transfer to the electrode.
Ideally, the sensors should be sensitive (low detection limits) and specific. For the gene probe, the extent of molecular complementarity between probe and target defines the specificity. In general, it is very difficult to obtain a perfect complementarity for targets with mismatches, since small variations in reaction conditions will alert the hybridization. It would be desirable to detect single molecule binding events with the specificity of a single base pair mismatch of a DNA.
Novel functional materials such as superlattice structures, quantum dots, nanowires, nanotubes, porous membranes, with or without attached functional groups, have been used as a sensing elements in combination with various possible detection mechanisms.
Some of the techniques take the advantage of the lengthwise similarity between the thickness of the superlattice layer and typical distance between bonding sites of biological and chemical molecules as well as between overall thickness of the superlattice structure and the length of such biological and chemical molecules. The surface binding of the biomolecules on the superlattice has been achieved by activating the superlattice by optical illumination or by electrical biasing; see for instance P. D. Brewer et al. US patent application publication US20050042773A1.
The other example of using the combination of the nanostructure, functionalized or not functionalized, and the spacing between the electrodes is a modified time of flight experiment. The ionic current is measured when the voltage biases are applied across the nanocapillary or nanotube. The electrophoretical flow of a single stranded polynucleotides through the structure blocks and reduces the ionic current. Time of flight of these polynucleotides vary linearly with their length, and different nucleotides will have different blocking signals, which will allow one to rapidly sequence the DNA (P. Yang et al. US patent application publication US20040262636A1).
There are also other devices where one or more voltage sources are coupled to each of the plurality of nano or micro sized regions on the semiconductor substrate. The one or more voltage sources selectively apply voltage to any one or more of the plurality of nano or micro sized regions to attract a particular molecule species to the one or more of the plurality of nano or micro sized regions (K. Code et al. US patent application publication US20050032100A1).
In one embodiment, complementary and non-complementary DNA is differentiated by measuring conductivity. Glass surface between two golden electrodes is modified by oligonucleotides complementary to the target DNA. Only complementary target DNA strands form nanoparticle assemblies between the two electrodes, and complete circuit by nanoparticle hybridization. This format is extended to substrate array, chips, with thousands of pairs of electrodes capable of testing for thousands of different nucleic acids (C. A. Mirkin et al. U.S. Pat. No. 6,828,432B2).
Active microelectronic arrays that use DC and AC fields for transport and positioning of biochemical molecules, DNA, biological cells, antibodies, polymers, etc. are fabricated with 25 to 10,000 test sites or micro-locations. An example is 100 test site chip commercialized by Nanogen, from San Diego, Calif. The chip has 80 microns diameter test sites/microlocations with underlying platinum microelectrodes, and twenty auxiliary outer microelectrodes. The outer group of microelectrodes provides encompassing electric field for concentrating charged particles in the active test area. On the similar device fluorescent nucleic acid molecules which are about 7 nm in length were transported back and forth over a distance of about 200 microns (K. Code et al. US patent application publication US20040158051A1).
There are many other applications of nanostructures, quantum dots, nanowires, nanotubes and superlattices for detection of biochemical molecules. However, their common characteristic is that they do not use quantum confinement in the sense it is applied in this invention. In all of the other applications, when used, the quantum confinement is related only to the optical detection methods. One of the examples is the selective infrared detection, where only the photons with energies equal to the difference of the energy levels can excite electrons. Another frequent quantum confinement application has been to eliminate energy momentum dispersion and to decrease phonon scattering rate and increase internal gain in a quantum dot based inter-sub band photoconductor (K. Code et al. US patent application publication US20040256612A1). The other application uses quantum dots that are substantially defect free, so that quantum dots exhibit photoluminescence with a quantum efficiency that is greater then 10 percent (H. W. H. Lee et al. US patent application publication US20050017260A1). In addition, there are number of sensors that rely on the use of particles and quantum dots, including magnetic particles, particularly for electrochemiluminescence detection (K. Code et al. U.S. Pat. No. 5,746,974; U.S. Pat. No. 5,770,459). Very recently the AlGaN/GaN heterostructures have been predicted to act as efficient biosensors detecting pH values of electrolytes, provided the two-dimensional electron gas lies close to the Ga oxide layer as in the case for N-face heterostructures (M. Bayer, C. Uhl, and P. Vogl, J. Appl. Phys. 97, 033703 (2005)). However, as it was said above, all of the examples enumerated do not use quantum confinement in a straight way applied in this invention.